3,4′,5-trihydroxy-stilbene-3-β-D-glucoside, also known as polydatin or resveratrol glucoside, is a known compound. China Patent Application No. 03117246, among other Chinese patents, describes the method of preparation of the Compound. However, the physicochemical parameters of 3,4′,5-trihydroxy-stilbene-3-β-D-glucoside as reported by different references vary widely. Examples are as follows:
Melting PointCrystallizationReferences(° C.)Solvent1. China Patent Application No.146~147Crystallization03117246by 55%~65%ethanol followedby washing withiced water2. Fulvia Orsini, Isolation, Synthesis,220~225CHCl3-MeOHand Antiplatelet Aggregation Activity9:1of Resveratrol3-O-β-D-Glucopyranoside andRelated Compounds, J. Nat. Prod.1997, 60, 1082~1087, (in thereference of this paper, Hillis W E,Ishikura K, J Chromatogr, 32, 323(1968), the melting point is indicatedto be 228~230° C.)3, Gamini S. Jayatilake. Kinase135~13720%~50%Inhibitors From PolygonumMeOH—H2OCuspidtum. Journal of NatureProducts. 1993, 56(10), 1805-110. (inthe reference of this paper, M. Antoni,D. M. X. Donnelly, Phytochemistry,15, 200 (1976), the melting point isindicated to be 130~140° C.)4. Chunru Ji and Yuming Wang,130~140,30% MeOH—H2OExperimental techniques and225~226Dissolved byExperiments of Chemistry of Chinese(doubleheating followedMedicine, Henan Publishing House ofmeltingby beingScience & Technology, 1986, p. 285.points)concentrated tocrystallize5. Yuming Kan et. al., Experimental223~22630% MeOH—H2O/Operation Techniques of Chemistry(decomposed)30% EtOH—H2Oof Chinese Medicine, MedicalScience and Technology PublishingHouse of China, 1986, p. 153.
The melting points of 3,4′,5-trihydroxy-stilbene-3-β-D-glucoside as reported by the above references vary widely, and the melting ranges are in most cases as wide as 5˜10° C. At present, no systemic research and/or interpretation is available regarding the differences in the physicochemical properties of 3,4′,5-trihydroxy-stilbene-3-β-D-glucoside as reported by different references. The inventors have discovered for the first time that 3,47,5-trihydroxy-stilbene-3-β-D-glucoside shows complex polymorphism, and the crystals of 3,4′,5-trihydroxy-stilbene-3-β-D-glucoside conventionally prepared according to the references are mostly a mixture of complex polymorphic crystals and/or amorphous powders, which accounts for the generally wide melting range that is measured, and even the appearance of double melting points.
It is known that the crystalline form of a drug will have influences on the dissolution rate, solubility, hygroscopicity, stability, biosorption and even bioactivity of the drug. Therefore, the crystalline form of a drug will significantly influence the drug activity, especially that of solid oral formulations, including, inter alia, drug therapeutic activity and adverse effects. In addition, the crystalline form of a drug will affect the bulkiness of the drug, which will further influence such formulating techniques as mixing, filling, milling, pelletizing, drying, tableting and the like, and even will possibly influence aspects in close relation to application of the drug, such as the storage life of the drug.
Generally speaking, for use in drug, especially in solid drug formulations, active substances should have defined physical forms and definite physicochemical properties. Inconsistency in the physical forms and/or physicochemical properties of the active substances may lead to difficulties in the formulating techniques of solid formulations or even liquid formulations, and difficulties in the clinical use of the formulations final products due to inhomogeneous properties. It is therefore obvious that stable supply of 3,4′,5-trihydroxy-stilbene-3-β-D-glucoside with definite physicochemical properties is both theoretically and practically important for the preparation of formulations, especially solid formulations, of the Compound.